Hou et al. BMC Medicine(2020) 18:216
https://doi.org/10.1186/s12916-020-01673-z

CORRESPONDENCE

Open Access

New insights into genetic susceptibility of
COVID-19: an ACE2 and TMPRSS2
polymorphism analysis
Yuan Hou1, Junfei Zhao2, William Martin1, Asha Kallianpur1,3, Mina K. Chung3,4,5, Lara Jehi5, Nima Sharifi3,5,
Serpil Erzurum3,5, Charis Eng1,3,6,7 and Feixiong Cheng1,3,7*Abstract
Background: Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity andmortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer andcardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2
and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, butthese factors are largely unknown.
Main body: In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in
ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic
susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be
associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, suchas p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including
p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations fordifferential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the highrisk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective
treatments (i.e., hydroxychloroquine and camostat) for COVID-19.
Conclusion: This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic
susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.
Keywords: Angiotensin-converting enzyme 2 (ACE2), Coronavirus, COVID-19, Genetic susceptibility, SARS-CoV-2,
TMPRSS2* Correspondence: chengf@ccf.org
1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic,
Cleveland, OH 44195, USA
3
Department of Molecular Medicine, Cleveland Clinic Lerner College ofMedicine, Case Western Reserve University, Cleveland, OH 44195, USA
Full list of author information is available at the end of the article© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Hou et al. BMC Medicine(2020) 18:216

Background
Coronaviruses (CoVs), so named for their “crown-like”
appearance by electron microscopy, are a large family ofviruses that spread from animal hosts (e.g., bats, civet,cats) to humans, causing life-threatening respiratory diseases like Middle East respiratory syndrome (MERS) andsevere acute respiratory syndrome (SARS) [1]. As of June18, 2020, over 8.4 million cases and 450,000 deaths
resulting from infection by a novel SARS coronavirus,
SARS-CoV-2 (also termed Coronavirus Disease 2019 or
COVID-19), have now been confirmed worldwide; furthermore, there have been more than 2.2 million confirmed cases and over 110,000 deaths due to the
COVID-19 pandemic in the USA alone [2]. Unlike other
CoVs, SARS-CoV-2 has had much larger global spreadand has impacted more people than SARS-CoV-1 and
MERS-CoV combined [1]. Morbidity and mortality due
to COVID-19 rise dramatically with age and co-existing
health conditions, including cancer and cardiovasculardiseases, and while most infected individuals recover,even very young and otherwise healthy patients may unpredictably succumb to this disease [3]. These observations beg the question of how much of the variation in
COVID-19 disease severity may be explained by genetic
susceptibility. Human genetic factors may contribute to
the extremely high transmissibility of SARS-CoV-2 andto the relentlessly progressive disease observed in a small
but significant proportion of infected individuals; yet,these factors are largely unknown. Development of new
preventive and/or therapeutic strategies for COVID-19
will be greatly facilitated by systematic identification ofhost genetic pathways and DNA polymorphisms (variants) which modulate the risk of infection and severe illness, including the overexuberant immune response to
the virus that often portends a poor outcome.
Not only has the COVID-19 pandemic had huge
health and economic impacts in 188 countries/regions
across the world, but the disease has also struck in different racial/ethnic subpopulations. Large genetic studies
in populations of geographically diverse ancestry havedemonstrated substantial genetic variation in proteincoding regions, with widely varying allele frequencies[4]. SARS-CoV-2 infection depends on the host cell factors angiotensin-converting enzyme 2 (ACE2) for entry
into cells and the host transmembrane serine protease
TMPRSS2 for SARS-CoV-2 spike (S) protein priming [5](Fig. 1a). ACE2, encoded on the X-chromosome, catalyzes the conversion of angiotensin II to angiotensin-(1–7), which acts as a vasodilator and exerts important
modulatory effects on the cardiovascular system.
TMPRSS2 is a key gene in prostate cancer, as an associated translocation drives ETS-family oncogene expression in a large proportion of tumors [6]. The
distribution of ACE2 expression has recently been

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investigated by single-cell RNA sequencing, and the expression of both ACE2 and TMPRSS2 are likely to dictate SARS-CoV-2 tissue tropism [7]. Clinical studies
have reported that incidence and mortality rates are significantly different between male and female COVID-19
patients, and the disease is associated with pre-existing
conditions, such as cancer and cardiovascular disorders,in particular individuals with hypertension receiving
anti-hypertensive medications [8]. Therefore, a systematic investigation of the functional polymorphisms in
ACE2 and TMPRSS2 among different populations could
pave the way for precision medicine and personalized
treatment strategies for COVID-19.

ACE2 polymorphism analysis across different
populations
Here, we investigated genetic susceptibility to COVID19 by examining DNA polymorphisms in ACE2 (OMIM
300335) and TMPRSS2 (OMIM 602060) genes. We assembled a total of 437 non-synonymous singlenucleotide variants (SNVs) in the protein-coding regionsof ACE2 and TMPRSS2 (Fig. 1a) from three databases:(i) Genome Aggregation Database (gnomAD v3: gnomad.broadinstitute.org, covering 9 geographical areas),(ii) Exome Sequencing Project (ESP: evs.gs.washington.
edu/EVS/), and (iii) 1000 Genomes Project (1KGP, www.
internationalgenome.org). We used ANNOVAR [9] toannotate all non-synonymous variants. By applying Polyphen2 and CADD (Combined Annotation Dependent
Depletion) scores, we identified 63 potentially deleterious variants in ACE2 (61 in gnomAD) and 68 deleterious variants in TMPRSS2 (63 in gnomAD).
We found that the distribution of deleterious variants
in ACE2 differs among 9 populations in gnomAD (v3).
Specifically, 39% (24/61) and 54% (33/61) of deleterious
variants in ACE2 occur in African/African-American(AFR) and Non-Finnish European (EUR) populations,
respectively (Fig. 1b). Prevalence of deleterious variants
among Latino/Admixed American (AMR), East Asian(EAS), Finnish (FIN), and South Asian (SAS) populations
is 2–10%, while Amish (AMI) and Ashkenazi Jewish(ASJ) populations do not appear to carry such variants
in ACE2 coding regions (Fig. 1b). Specifically, several
variants, including p.Met383Thr, p.Pro389His, andp.Asp427Tyr, have been reported to slightly inhibit theinteraction between ACE2 and the spike protein of
SARS-CoV-1 [10], which caused the first global SARSCoV-1 outbreak. Only AFR populations carryp.Met383Thr and p.Asp427Tyr variants, with allele frequencies of 0.003% and 0.01%, respectively (Fig. 1b). The
p.Pro389His only occurs in the AMR populations, withan allele frequency of 0.015%. The p.Arg514Gly is a low
allele frequency (0.003%) variant in AFR populations andis also somatically mutated in colon cancers andHou et al. BMC Medicine(2020) 18:216

Fig. 1 (See legend on next page.)

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Hou et al. BMC Medicine(2020) 18:216

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(See figure on previous page.)
Fig. 1 The coding-region variants in ACE2 and TMPRSS2 from ~ 81,000 human genomes across 8 populations. a Coding-region variants in thegenes encoding angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) across three human genome
databases: (i) Genome Aggregation Database (gnomAD v3), (ii) Exome Sequencing Project (ESP), and (iii) 1000 Genomes Project (1KGP). SARSCoV-2 utilizes the host cell factors angiotensin-converting enzyme 2 (ACE2) for entry into cells and the host transmembrane serine protease
TMPRSS2 for SARS-CoV-2 spike (S) protein priming, offering potential pathway for therapeutic development in treatment of COVID-19. b
Distribution of 61 deleterious variants in the ACE2 coding region identified in gnomAD (v3). Polyphen2 > 0.96 and CADD scores > 20 as cutoff
identify putative deleterious variants. The upper panel using 3 colors shows the functional domains of ACE2, and the height of the vertical line
represents the number of populations that carry this variant. The lower heatmap shows the allele frequencies (color key) of a variant acrossdifferent populations. c Distributions of 63 putative deleterious variants in the TMPRSS2 coding region using the same approach of b. AFR,
African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish
European; SAS, South Asian; PNA, population not assigned

melanomas from The Cancer Genome Atlas (TCGA:
https://portal.gdc.cancer.gov). This ACE2 variant is located in the angiotensinogen (AGT)-ACE2 interaction
surface, which is anticipated to influence the reninangiotensin system (RAS) function. The RAS is critical
for regulation of blood pressure, sodium, and fluid balance, and its dysfunction is associated with cardiovascular and kidney disorders [11]. Residues Arg708/710/716
are located in the dimeric interface of ACE2 (Fig. 2a),and they are essential for its cleavage by TMPRSS2; thisprocessing is required for augmentation of SARS-Sdriven entry into host cells [12]. The EUR population
carries the p.Arg708Trp, p.Arg710Cys, p. Arg710His,
and p.Arg716Cys variants with allele frequency of
0.01~0.006% (Fig. 1a), while the EAS and the AMR populations only carry p.Arg708Trp and p.Arg710His withallele frequency of 0.04% and 0.01% respectively. In
addition to these four variants, p.Leu731Phe has thehighest allele frequency in the AFR and EUR populations. We further inspected the expression quantitative
trait loci (eQTL) for ACE2 using the GTEx [13] andQTLbase [14] databases. We did not find any eQTLs for
ACE2 from the GTEx, while we found one weak eQTL
associated
with
ACE2
non-synonymous
SNP(rs41303171) in the kidney from the QTLbase [14].
Altogether, these comparative genetic analyses suggestthat ACE2 genomic variants may play important roles insusceptibilities to COVID-19 and its associated cardiovascular conditions by altering AGT-ACE2 pathway (i.e.,p.Arg514Gly). In addition to differential polymorphisms
which may explain susceptibility and even outcome indifferent ethnic populations, the fact that ACE2 is localized to Xp22.2 may help explain the observed maleassociated risk. As such, even in the absence of variationin this gene, the monoallelic versus biallelic presence of
this gene may impact the natural history and prognosis
of COVID-19 in males.

TMPRSS2 polymorphism analysis across different
populations
TMPRSS2 enzyme activity is important for coronavirus
spread and pathogenesis in the infected host [15]. Our

analysis indicates 4% (11/274) of non-synonymous variants of TMPRSS2 are stop-gained mutations and carriedby AFR and EUR with low allele frequency (7.0 ×
10−6~1.4 × 10−5). Meanwhile, 35% (22/63) and 59% (37/63) of deleterious variants in TMPRSS2 coding regions
are carried by the AFR and EUR populations from gnomAD (v3), respectively (Fig. 1c). Each of the EAS, SAS,and FIN populations only carries 4 deleterious variants.
We found 6 germline deleterious variants (p.Val160Met,
p.Gly181Arg, p.Arg240Cys, p.Gly259Ser, p.Pro335Leu,
and p.Gly432Ala) in the TMPRSS2 coding region, which
are also identified as somatic mutations occurring in different cancer types from TCGA and COSMIC databases(https://cancer.sanger.ac.uk/cosmic).
We further evaluated the eQTL profile of TMPRSS2
using the GTEx [13] and QTLbase databases [14] aswell. We found two eQTLs associated with TMPRSS2
non-synonymous SNPs (rs12329760 (encoding p.Val160Met), p = 4.54 × 10−5; rs75603675, p = 0.009) in the kidney and bone, respectively, using the QTLbase database[14], while there are no known eQTLs associated withTMPRSS2 non-synonymous SNPs from GTEx [13]. Notably, all populations carry p.Val160Met variants with thehighest allele frequency (~ 25%), especially for the EAS
population at a 40% allele frequency. Asp435 is a key
residue for catalytic substrate binding of TMPRSS2(Fig. 2b). We found that the p.Asp435Tyr, which has
low allele frequency, is carried by the EUR population
only (Fig. 1c). These unique but prevalent polymorphisms in TMPRSS2 offer potential explanations for differential genetic susceptibility to COVID-19 as well as
for risk factors, including those with cancer and thehigh-risk group of male patients. Because TMPRSS2 islocated on 21q22.3, we could speculate that individuals
with Down syndrome would be at high risk for COVID19 infection. In addition, oncogenic roles of TMPRSS2
may be linked to poor outcomes with COVID-19 as well[16], which should be studied in the future. Using
single-cell RNA-sequencing analysis, Schuler et al.
showed that TMPRSS2 expression was highest in ciliatedcells and type I alveolar epithelial cells (AT1) and increased with aging in humans and mice [17]. This

Hou et al. BMC Medicine(2020) 18:216

Fig. 2 (See legend on next page.)

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Hou et al. BMC Medicine(2020) 18:216

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(See figure on previous page.)
Fig. 2 Structural view of the coding-region variants in ACE2 and TMPRSS2 and a proposed pharmacogenomics model of effective combination
therapies for COVID-19. a Full-length structures of the sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19, red)–ACE2 (blue)
heterodimer in its homodimeric form complexed with the receptor binding domain (RBD, mint) of SARS-CoV-2 (PDB ID: 6M17). Highly deleterious
variants are labeled as yellow spheres on ACE2. Insets depict mutations in residues 383 through 427 (top) and residues 708 through 731(bottom). b Homology model of the catalytic chain (256–492) of TMPRSS2. Highly deleterious mutations are labeled as yellow spheres. c A
proposed model of effective combination therapies (i.e., hydroxychloroquine, E-64D (a protease inhibitor), and camostat mesylate (an approved
TMPRSS2 for treatment of chronic pancreatitis in Japan)) for COVID-19 by blocking ACE2 and TMPRSS2 across different populations with threegenotypes. Relationship among spike (S) protein of SARS-CoV-2, ACE2, and TMPRSS2 were shown as a triangle, with each pair connecting byphysical binding (double-headed arrow) or cleavage (single-headed arrow). We propose three hypotheses for COVID-19 therapeutic options: (i)for patients with wild-type or naïve expression of ACE2 and TMPRSS2, hydroxychloroquine (or chloroquine, or E-64D) combined with camostat
may offer more clinical benefit; (ii) for patients with polymorphisms or dysregulation on TMPRSS2, hydroxychloroquine or chloroquinemonotherapy may offer more clinical benefit; and (iii) for patients with polymorphisms or dysregulation on ACE2, the patients who might havemild symptoms can recover in a short period. All three pharmacogenomics models for COVID-19 must be validated both experimentally andclinically before being used in patientsobservation suggests that developmental regulation of
TMPRSS2 may link the relative protection of infants andchildren from COVID-19. Thus, it should be of greatinterest to investigate the age-related polymorphisms for
TMPRSS2, such as using the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort [18],in the future.

Host genetic factors guide personalized treatmentof COVID-19
There are currently no approved effective medications
against COVID-19. Several national and international research groups are working on the development of vaccines to prevent COVID-19, but effective vaccines not
likely to be available for many months. Several potentially repurposable drugs (Fig. 2c), including melatonin[19], hydroxychloroquine, and chloroquine, are under investigation for treatment of COVID-19 [20]. A primarymechanism-of-action of hydroxychloroquine and chloroquine is to inhibit virus entry by targeting the endosomal
pathway [20]. Hydroxychloroquine and chloroquine is
known to increase the pH of endosomes, which inhibits
membrane fusion, a required mechanism for viral entry
into the cell [21]. Additionally, inhibition of SARS-CoV2 could be due to differential glycosylation of both
ACE2 and the spike protein [21]. As shown in Fig. 1b,
several variants identified in the AFR and AMR populations, including p.Met383Thr, p.Pro389His, andp.Asp427Tyr (the pathogenic variants in ACE2 slightly
inhibit interaction with the S protein), may influence theclinical efficacy of hydroxychloroquine or chloroquine.
This may help explain why treatment of hydroxychloroquine was not significantly associated with difference inin-hospital mortality [22]. However, further pharmacogenomic studies that integrate drug response and genetic
data from patients with COVID-19 are urgently needed.
In addition to the endosomal pathway, fusion of viraland host cellular membranes through S protein conformational changes is another way for coronavirus

entry into the host cell [23]. This process can be blocked
by a TMPRSS2 inhibitor (camostat mesylate, a drug approved in Japan) [5]. The mechanisms whereby
TMPRSS2 promotes cellular entry of SARS-CoV-2 canbe summarized by two aspects based on its proteolytic
function (Fig. 2). The first is S protein cleavage at S1/S2and S2’ sites, which might be the reason why SARSCoV-2 entry into cells depends on TMPRSS2. The infection and pathogenesis of SARS-CoV-2 depends on thepresence of TMPRSS2, in the face of the cellular elevated pH environment [5, 24, 25]. The inhibitors ofendosomal acidification such as CatB/L inhibitor E-64D
and hydroxychloroquine/chloroquine may only work for
TMPRSS2-absence patients who are infected by SARSCoV-2, and may have less effect or no effect for the patients with wild-type of TMPRSS2 [5, 24]. Therefore, theEUR and AFR populations might be more sensitive tohydroxychloroquine or chloroquine by carrying missense
variants and stop-gained variants on TMPRSS2 (Figs. 1cand 2c). Yet, for patients who have wild-type of ACE2
and TMPRSS2, a combination of camostat with hydroxychloroquine or chloroquine may have better clinicalbenefit. However, all discussed treatment strategies must
be validated by randomized controlled trials before clinical use. The second mechanism is cleavage of ACE2 by
TMPRSS2 at Arginine 697 to 716 [12], which enhances
viral uptake. Thus, the EUR population withp.Arg708Trp,
p.Arg710Cys,
p.Arg710His,
andp.Arg716Cys variants in ACE2 may have mild symptoms
after SARS-CoV-2 infection as ACE2 loses the cleavage
site by TMPRSS2 and changes the ACE2 dimer formation [26] (Fig. 2c).

Discussion and future directions: call for hostgenetics initiative for COVID-19
A few limitations merit consideration. Current analysis
examined massive genomic data from general population, not COVID-19 patient-specific populations. All
genetic associations identified in current study areHou et al. BMC Medicine(2020) 18:216

urgently needed to be tested in COVID-19 patients inthe near future. As the high-resolution protein structureof TMPRSS2 is not yet available, further functional observations and clinical validation are warranted for all
abovementioned genetic and pharmacogenomics findings. We anticipate that large-scale genome-wide association studies (GWAS) are urgently needed to identify
likely causal host genetic risk factors for severe COVID19 outcomes using genetic data from patients with
COVID-19; such knowledge will improve risk stratification of individuals exposed to or testing positive for
SARS-CoV-2 and allow for precision medicine interventions for COVID-19. A COVID-19 host genetics initiative is already underway to bring together the human
genetics research community to generate, share, andanalyze data in a search for the genetic determinants of
COVID-19 susceptibility, severity, and outcomes [27].
The first COVID-19 GWAS identified the 3p21.31 genecluster (including SLC6A20, LZTFL1, CCR9, FYCO1,CXCR6, and XCR1) as a genetic susceptibility locus insevere patients with COVID-19 and respiratory failure[28]. Yet, our study aims to look for SNPs associatedwith disease severity of COVID-19, but not disease susceptibility. In summary, systematic identification of thegenetic determinants of COVID-19 susceptibility, severity, and clinical outcome, including both virus and hostfactors (e.g., ACE2 and TMPRSS2 polymorphisms), could
guide personalized treatment in the emerging COVID19 pandemic and even explain current epidemiologic observations (i.e., males, elderly at high risk, and clinicalcomorbidities) and natural history.

Conclusions
This comprehensive comparative genetic analysis of approximately 81,000 human genomes suggested possible
associations of ACE2 and TMPRSS2 DNA polymorphisms with COVID-19 susceptibility, severity, and clinical outcomes. We found that ACE2 polymorphisms
were more likely to be associated with cardiovascularandpulmonaryconditions
byalteringtheangiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique
but prevalent polymorphisms in TMPRSS2, including
p.Val160Met (rs12329760), may provide potential explanations for differential genetic susceptibility to COVID19 as well as for risk factors, including cancer and thehigh-risk group of male patients. We highlighted thatpolymorphisms in ACE2 or TMPRSS2 could guide personalized treatments (i.e., hydroxychloroquine andcamostat) for COVID-19. In summary, this study suggested that ACE2 or TMPRSS2 DNA polymorphisms
were likely associated with genetic susceptibility to
COVID-19, which calls for a human genetics initiativefor fighting the COVID-19 pandemic.

Page 7 of 8

Abbreviations
1KGP: 1000 Genomes Project; ACE2: Angiotensin-converting enzyme 2;
CoV: Coronavirus; COVID-19: Coronavirus Disease 2019; eQTL: Expression
quantitative trait loci; gnomAD: Genome Aggregation Database;
MERS: Middle East respiratory syndrome; SARS: Severe acute respiratory
syndrome; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2;
ESP: Exome Sequencing Project; S: Spike; TMPRSS2: Transmembrane serine
protease 2
Acknowledgements
We thank all helpful discussions and critical comments regarding thismanuscript from the COVID-19 Research Intervention Advisory Committee
members at the Cleveland Clinic. SCE is the Alfred Lerner Memorial Chair of
Innovative Research and CE is the Sondra J. and Stephen R. Hardis Endowed
Chair of Cancer Genomic Medicine at the Cleveland Clinic.
Authors’ contributions
F.C. conceived the study. Y.H., J.Z., and W.M. performed all experiments anddata analysis. A.K., M.K.C, N.S., L.J., C.E., and S.E. discussed and interpreted all
results. F.C., Y.H., C.E., and S.E. wrote and critically revised the manuscript with
contributions from other co-authors. All authors read and approved the final
manuscript.
Funding
This work was supported by the National Heart, Lung, and Blood Institute of
the National Institutes of Health (NIH) under Award Number R00HL138272
and the National Institute of Aging under Award Number R01AG066707 to
F.C. This work was supported, in part, by the VeloSano Pilot Program(Cleveland Clinic Taussig Cancer Institute).
Availability of data and materials
All population genetic data used in this study are free and available at threedatabases: (i) Genome Aggregation Database (gnomAD v3: gnomad.
broadinstitute.org, covering 9 geographical areas), (ii) Exome Sequencing
Project (ESP: evs.gs.washington.edu/EVS/), and (iii) 1000 Genomes Project(1KGP, www.internationalgenome.org).
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The content of this publication does not necessarily reflect the views of theCleveland Clinic. The authors declare no competing interests.
Author details
1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic,
Cleveland, OH 44195, USA. 2Department of Systems Biology and Departmentof Biomedical Informatics, Herbert Irving Comprehensive Center, Columbia
University, New York, NY 10032, USA. 3Department of Molecular Medicine,
Cleveland Clinic Lerner College of Medicine, Case Western Reserve University,
Cleveland, OH 44195, USA. 4Department of Cardiovascular Medicine, Heart,
Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
5
Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
6
Department of Genetics and Genome Sciences, School of Medicine, Case
Western Reserve University, Cleveland, OH 44106, USA. 7Case Comprehensive
Cancer Center, School of Medicine, Case Western Reserve University,
Cleveland, OH 44106, USA.
Received: 25 April 2020 Accepted: 22 June 2020

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